Table 1.
Characteristics and efficacy of clinical trials investigating the role of omega-3 fatty acids in reducing risk of early and any PTB.
| Ref. | Study | Ingredient, Daily Dosage | Main Results | Comments | |||
|---|---|---|---|---|---|---|---|
| Objective | Design | Population/Sample Size | Duration | ||||
| Carlson et al. 2013 [76] | To assess if DHA supplementation can increase maternal and newborn DHA status, gestation duration, birth weight, and length | RCT, DB, PC. | Healthy pregnant women between 8 and 20 weeks of gestation from the USA, n = 350 | <20 weeks of gestation until delivery | Intervention: 3 capsules/day of a marine algae-oil source of DHA (600 mg DHA/day) Placebo: 3 capsules containing half soybean and half corn oil |
Compared to placebo, DHA supplementation resulted in: (1) Longer gestation duration (2.9 day; p = 0.041). (2) Fewer infants born <34 weeks of gestation (p = 0.025). EPTB reduced by 87.5%. (3) Shorter hospital stays for PT infants (40.8 compared with 8.9 day; p = 0.026). (4) Similar PTB incidence between groups, with more EPTB in the placebo group (4.8% vs. 0.6%, p = 0.025). (5) Greater birth weight (172 g; p = 0.004), length (0.7 cm; p = 0.022), and head circumference (0.5 cm; p = 0.012). (6) Higher maternal and cord Red Blood Cell-phospholipid-DHA (2.6%; p < 0.001). |
Women taking supplements <300 mg DHA/day were not excluded. Dietary n−3 LC-PUFA intakes were not assessed Many secondary variables were studied but without adjustment for multiple comparisons. Incidence of PTB and EPTB were secondary outcomes. |
| Makrides et al. 2010 [77] | To assess if DHA supplementation during the last half of pregnancy has a beneficial effect on maternal depressive symptoms and child neurodevelopment | RCT, DB, PC. | Healthy pregnant women <21 weeks gestation from Australia n = 2399 | <21 weeks of gestation until delivery | Intervention: 3 capsules/day of DHA-rich fish oil concentrate (800 mg DHA/day A + 100 mg EPA/day) Placebo: 3 capsules/day of vegetable oil containing a blend of rapeseed, Sunflower, and palm oil |
Compared to placebo, DHA+EPA supplementation resulted in (1) No differences in the rate of women with depressive symptoms, as well as the cognitive and language composite scores of their children. (2) A small to modest increase in the duration of gestation (precise estimate of effect size could not be determined due to obstetric interventions). (3) Fewer infants born <34 weeks gestation (1.09 % vs. 2.25% adjusted Relative Risk (RR), 0.49; p = 0.03), and association with fewer low birth weight infants and fewer admissions to neonatal intensive care. EPTB was reduced by 51.6%. |
Dietary intake of n-3 LC-PUFAs was not assessed. The study failed to demonstrate an improvement in primary outcomes such as reduction in depressive symptoms among women and improvement in cognitive and language scores of their children. |
| Ramakrishnan et al. 2010 [78] | To assess if prenatal DHA supplementation increases gestational age and birth size | RCT, DB, PC. | Healthy pregnant women from 18 to 22 weeks of gestation from Mexico n = 1094 |
From 18 to 22 weeks of gestation until delivery | Intervention: 2 capsules/day of 200 mg of DHA derived from an algal source (400 mg DHA/day) Placebo: 2 capsules/day containing olive oil |
Compared to placebo, DHA supplementation resulted in (1) No differences in mean gestational age, PTB, weight, length and head circumference at birth. |
|
| Helland et al. 2001 [79] | To evaluate the effect of n-3 or n-6 long-chain PUFAs on birth weight, gestational length, and infant development | RCT, DB, PC. | Healthy, nulli- or primiparous women in weeks 17 to 19 of pregnancy from Norway n = 590 |
17 to 19 weeks of gestation until 3 months after delivery | Intervention: 10 mL/day of cod liver oil, providing around 2 g daily of the long chain omega-3 fatty acids. Placebo: 10 mL/day of corn oil, providing around 5 g daily of omega-6 fatty acid linoleic acid. |
In comparison with placebo, cod liver oil supplementation resulted in (1) No differences in gestational length or birth weight, length or head circumference. (2) Higher concentrations of n-3 fatty acids EPA, DHA, and DHA in umbilical plasma phospholipids. (3) Neonates with high concentration of DHA in umbilical plasma phospholipids (upper quartile) had longer gestational length than those with low concentration (lower quartile; 282.5 (8.5) vs. 275.4 (9.3) days). |
Substantial numbers of women excluded from the two groups post randomization due to withdrawals. It does not mention gestational lengths to facilitate undertaking of an ITT analyses. In this population, baseline intake of long-chain n-3 fatty acids was estimated to be relatively high (0.5 g/day) and less than one 1% had a PTB. |
| Olsen et al. 2000 [80] | To test the preventive effects of dietary n-3 fatty acids on Pre-term delivery, Intrauterine growth retardation, and pregnancy-induced hypertension |
Multicenter RCT, PC (4 prophylactic + 2 therapeutic trials) | High risk pregnancies from 19 hospitals in 7 different countries in Europe Four prophylactic trials: previous pre-term (n = 232), IUGR (n = 280), PIH (n = 386) and twin pregnancies (n = 579) Two therapeutic trials: threatening pre-eclampsia (n = 79) and suspected IUGR (n = 63) |
From ~20 weeks (prophylactic trials) or 33 weeks (therapeutic trials) until delivery. | Intervention: prophylactic trials (4 capsules/day of fish oil, 1.3 g EPA and 0.9 g DHA) and therapeutic trials (9 capsules/day of fish oil, 2.9 g EPA and 2.1g DHA) (32% EPA, 23% DHA, 2 mg tocopherol/mL) Placebo: identical looking capsules of olive oil (72% oleic acid, 12% linoleic acid) |
Compared to placebo, fish oil supplementation resulted in the following among women with a previous Pre-term delivery in the prophylactic trial: (1) Reduced recurrence risk of PTB from 33% to 21% (Odds Ratio (OR) 0.54 (95% Confidence Interval (CI) 0.30–0.98)) (2) Reduced recurrence risk of EPTB from 13.3% to 4.6% (OR 0.32 (95% CI 0.11–0.89)). (3) Longer mean gestational length by 8.5 day (95% CI 1.9–15.2. (4) No effect on PTB in twin pregnancies. |
|
| Onwude et al. 1995 [81] | To determine whether n-3 fatty acid (EPA/DHA) prophylaxis is beneficial in high-risk pregnancies | RCT, DB, PC. | Pregnant women at high risk of developing PIH and asymmetrical IUGR from an antenatal clinic from UK n = 233 |
From around 25 weeks of gestation until 38 weeks of gestation |
Intervention: 9 capsules/day of fish oil providing 2.7 g omega-3 fatty acids/day (1.62 g of EPA and 1.08 g of DHA) Placebo: matching air-filled capsules |
Compared to placebo, fish oil supplementation resulted in (1) No difference in the duration of gestation or other outcomes such as proteinuric PIH, non-proteinuric PIH, or birth weight within the lowest 3% on the growth charts. |
This study failed to support the hypothesis that fish oil supplementation improved pregnancy outcome in an at risk population for impaired fetal growth or PIH. |
| Bulstra Ramakers et al. 1995 [82] | To study the effects of adding 3 g/day of EPA to the diet, on recurrence rate of IUGR and PIH in a high-risk population | RCT, DB, PC. | Pregnant women with a history of IUGR with or without PIH in the previous pregnancy from the Netherlands n = 63 |
From 12 to 14 weeks of gestation until delivery | Intervention: 4 capsules 3 times daily, which corresponded to a daily dose of 3 g of EPA Placebo: Identical capsules with coconut oil |
Compared to placebo, EPA supplementation resulted in (1) No difference in the rates of PTB |
No information was provided about content of DHA No estimate of mean gestational length was provided |
| Olsen et al. 1992 [83] | To study the effect of a fish-oil supplement, a control olive-oil supplement, and no supplementation on pregnancy duration, birthweight, and birth length | RCT | Healthy pregnant women from Denmark n = 533 | From gestation week 30 until delivery | Intervention: Four 1 g fish oil capsules/day containing 2.7 g n-3 fatty acids- 32% EPA, 23% DHA, 2 mg tocopherol Placebo: Four 1 g olive oil capsules/day No supplement group |
Compared to placebo fish oil supplementation resulted in: (1) The highest mean length of gestation when all 3 groups were compared in a single analysis (fish oil, olive oil and no supplement: 283, 279.4 and 281.7 days respectively, p = 0.006). (2) On an average 4 days longer pregnancies in the fish-oil group compared to the olive oil group (95% CI: 1.5–6.4, p = 0.005). (3) The effect seemed to depend on the baseline intake of fish. -Among those 20% of the women who had the highest intake of fish at randomization, no difference could be detected between the oil groups. -In those 20% who had the lowest intake for fish, a difference of 7.4 days was observed (95% CI 2.2–12.6 days, p = 0.01). -In the middle 60%, the groups differed by 4.8 days (95 CI 1.8–7.8, p = 0.005). |
Maternal baseline dietary intake could explain differences in the duration of gestation and higher intakes may have a saturating effect |
| Mardones et al. 2008 [84] | To study the effect of maternal food fortification with omega-3 fatty acids and multiple micronutrients on birth weight and gestation duration | Non-blinded, RCT, PC. | Healthy pregnant women up to 20 weeks Gestation from Chile n = 972 |
From up to 20 weeks of gestation until delivery | Intervention: 2 kg/month of powdered milk fortified with multiple micronutrients and both a-linolenic acid and linoleic acid; iron was supplied in an amino-chelated form Placebo: 2 kg/month powdered milk fortified with small amounts of iron sulphate, copper, zinc, and vitamin C. |
Based on ITT analyses and in comparison with placebo, the intervention resulted in (1) Lower incidence of EPTB (0.4% vs. 2.1%; crude OR (95% CI): 5.26 (1.08–34.90), p = 0.02). (2) Increase in gestation duration (1.40 days difference, 95% CI: -0.02–2.82 d, p = 0.05). (3) Higher mean birth weight (65.4 g difference, 95% CI: 5–126 g; p = 0.03). (4) Higher infant length (0.37 cm difference, 95% CI: 0.06–0.68 cm, p = 0.019). |
Impossibility to perform a blinded design and have strict control of compliance with the prescribed amounts of the products taken to the homes of the study subjects Slight difference in gestational age at recruitment Associations with gestation duration would need a larger sample size for confirmation (the statistical power reached only 0.61 in ITT analyses) |
| Smuts et al. 2003 [85] | To assess whether higher intake of DHA would increase duration of gestation and birth weight in US women | RCT, DB, PC. | Healthy pregnant women between the 24th and 28th week of pregnancy from the US (predominant black population) n = 291 |
From 24–28 weeks of gestation until delivery | Intervention: 1 DHA enriched egg/day (133 mg DHA) Placebo: 1 ordinary egg/day (33 mg DHA) |
Compared to the placebo group, the supplementation with DHA-enriched egg resulted in (1) Increased duration of gestation (6.0 ± 2.3 days, p = 0.009) (based on analyses adjusted for maternal BMI at enrollment and number of prior pregnancies). |
The unadjusted analysis showed a difference of 2.6 days (not statistically significant), while adjustment for maternal BMI at enrollment and number of prior pregnancies resulted in an increased duration of gestation by 6 days. The adjustments may have introduced a post hoc element into the interpretation of the result. |
BMI: body mass index, DHA: docosahexaenoic acid, EPA: eicosapentanoic acid, EPTB: early PTB, PTB: preterm birth, IUGR: intrauterine growth retardation, LC-PUFA: long-chain polyunsaturated fatty acids, PIH: pregnancy-induced hypertension, RCT: randomized controlled trial, DB: double blind, PC: placebo controlled.